The long-term objective of this study is a detailed understanding of the molecular mechanism by which reticulocyte binding ligand (RBL)-proteins mediate invasion of erythrocytes by the parasite Plasmodium falciparum, the causative agent of malarial infections in humans. This application focuses on the protein Reticulocyte Binding Protein Homolog 2b, or Rh2b, as a model protein of RBL family. During the blood-stage of malarial infection, a parasite adheres to an erythrocyte and then invades the erythrocyte. Invasion is the process by which the parasite enters the erythrocyte where it then undergoes several rounds of cell division before being released again into the blood-stream. Parasite invasion ligands, which are typically Type I transmembrane proteins, engage specific molecular receptors on the erythrocyte surface and are central to invasion. Rh2b coordinates a major pathway of invasion in many parasite strains. Recent studies have shown that the tail of Rh2b is required to specify the pathway of invasion by this RBL-protein. The studies described here are designed to define the molecular role of Rh2b during the process of invasion, and link the activity of the tail to intraparasitic processes that drive invasion. Specific Aim 1 seeks to understand how the tail of Rh2b controls both the strength of invasion as well as the specificity of the invasion pathway. Specific Aim 2 seeks to identify the essential features of the tail of Rh2b that confer function onto the invasion ligand. Specific Aim 3 seeks to identify parasite protein factors that physiologically interact with the tail of Rh2b. These studies will avail primarily of genetic and biochemical approaches. Malaria kills approximately one-million people each year and is associated with high morbidity. Invasion of erythrocytes by P. falciparum is a critical aspect of malarial infection in humans; this process is thus a high-priority drug or vaccine target. The experiments proposed in this study may illuminate important features of parasite molecules known to be critical to the invasion process.